title: Transient receptor potential channels function as a coincidence signal detector mediating phosphatidylserine exposure.
abstract: Blood platelet aggregation must be tightly controlled to promote clotting at injury sites but avoid inappropriate occlusion of blood vessels. Thrombin, which cleaves and activates Gq-coupled protease-activated receptors, and collagen-related peptide, which activates the receptor glycoprotein VI, stimulate platelets to aggregate and form thrombi. Coincident activation by these two agonists synergizes, causing the exposure of phosphatidylserine on the cell surface, which is a marker of cell death in many cell types. Phosphatidylserine exposure is also essential to produce additional thrombin on platelet surfaces, which contributes to thrombosis. We found that activation of either thrombin receptors or glycoprotein VI alone produced a calcium signal that was largely dependent only on store-operated Ca(2+) entry. In contrast, experiments with platelets from knockout mice showed that the presence of both ligands activated nonselective cation channels of the transient receptor potential C (TRPC) family, TRPC3 and TRPC6. These channels principally allowed entry of Na(+), which coupled to reverse-mode Na(+)/Ca(2+) exchange to allow calcium influx and thereby contribute to Ca(2+) signaling and phosphatidylserine exposure. Thus, TRPC channels act as coincidence detectors to coordinate responses to multiple signals in cells, thereby indirectly mediating in platelets an increase in intracellular calcium concentrations and exposure of prothrombotic phosphatidylserine.
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK. m.harper@bris.ac.uk
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Harper
authors.forename: Juan E Camacho
authors.initials: JE
authors.lastname: Londoño
authors.forename: Kathryn
authors.initials: K
authors.lastname: Quick
authors.forename: Julia Camacho
authors.initials: JC
authors.lastname: Londoño
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Philipp
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.forename: Alastair W
authors.initials: AW
authors.lastname: Poole
mesh_terms: D000328:Adult; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008954:Models, Biological; D010455:Peptides / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000074287:TRPC6 Cation Channel; D013830:Thiadiazoles / Q000494:pharmacology; D053778:Thiazolidines / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D055815:Young Adult
chemical_list: C487681:2-(4-(4-nitrobenzyloxy)benzyl)thiazolidine-4-carboxylic acid ethyl ester; C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000813:Anilides; D001593:Benzyl Compounds; D002352:Carrier Proteins; D010455:Peptides; D010718:Phosphatidylserines; D019831:Sodium-Calcium Exchanger; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; D013830:Thiadiazoles; D053778:Thiazolidines; C492146:Trpc6 protein, mouse; C435908:collagen-related peptide; D012964:Sodium; D013917:Thrombin; D002118:Calcium